Workbook for Organic Synthesis: The Disconnection Approach Second Edition Stuart Warren I{eader jn ()rganic C'henlistry, Departlnenl of Chenlistf)\ University of (~~unbridge U·K and llaul \Vvatt " Reader and l)irector of l Indcrgraduate Studies , School of lJ ni versity of BristoL lJ K (~WILEY A John \Nilcy ;1nd Sons, L.td., Pubbcatiol1 (~henlis1xy, This edition first published 2009 ~ 2009 John Wiley & Sons Ltd Re~i.\Nred ol.fice John Wil ey & Sons Ltd, The Atrium, Southern Gate, 'Chichester, West Sussex POl9 ~SQ, United Kingdom For details of our global editorial offices for customer services and for information about how to apply for permi ssion to reuse the copyright material in this book please see our wcb~ite at www.wiley.com The right of the author to he identified as the author of this work has been asserted in accoruance with the Copyright , Designs and Patents Act 19RR All lights reservcd No part of this publication may be rcproduced, stored in a retrieval system , or transmitteu, in allY form or by any means, electronic mechanical, photocopying rccoruing or othenvise, except as permitted by the UK Copyright Designs and Pat~nts \Viley Jiso publishcs its books in ;! \'ailable in dectronic books ;1 Act 19l-:R without the prior permission of the publisher variety or electronic formats Some conlent that appc;lrs in print may lIot be · \ Designations Llsed hy companies 10 distinguish their" rroduCls are often claimcd as trademarks All Immel names and product names used in this bo()k ;lIe tr;l(k 11;\l11eS, service marks trademarks or registered trademarks of tilc ir i"c',.; pccti\·c' l)\\llcrs The puhlisher i:; IIU( assoc"iJleJ \\itil OH 16a 8~C 14a HO 15a Rlit'rt' JI(,I!.I' So the disconnections also fall into place Just one C- O bond was disconnected at first 17b then one C-O and one C-C 16h and final ly the alkene was di sconnected 14h in what you may rec ogni se as an aldol reaction with formaldehyde If yo u practi se analysing published syntheses Iike this you wi II increase your llnderstandi ngof good bonds to disconnect ' 8~ o 17b 'I '3 ~ :::::; OH 1Gb 14b References W E Gore G T Pearce and R M Sil\"crslcin OIR- Cheill , 1975 40 1705 13b 39 Aromatic Hctl'rocvc/cs 2S0 A Synthesis of Quil1oline.\' and of Fused lmidaz,o-Pyridines The angiotensin II inhibitor 49 for the treatment of ' hypertension combines these two ring systems.l) Disconnection somewhere in the middle 49 gives much simpler starting materials 50 and 52 and we'll look at each of these The quinoline 52 is the easier ProbJem 39.4: Using only standard C-N and C-C disconnections, suggest a synthesis of 5i :~ HN~ ~ y~ :_ Me + C-N ===> I C-Br C0 H C02 H r , ==='.> C0 H I ! ~ I' ' N H N H 50 49 I: r 52 51 Answer 39.4: Straightforward! Lactam disconnection 52a reveals an obvious a1dol condensation product 53 between some derivative of malonic acid 55 and the ketone 54 Me Me ~CO'H UN~O Me c-c C-N ===> ===> C0 2H aldol amide (C0 H + C0 H C0 H NH2 H !' 52a 54 53 55 In fact the half ester, half acid chloride of malonic acid 56 was used in condensation with 54 to give the ester 57 and this was cyclised to 58, the ester of 52, which was used in the rest of the synthesis We shall return shortly to the synthesi s of 54 after the next section Ar (C0 2Et COCI 56 54 CH 2CI N~C02Et r ((COA' ~ I H 57; Ar = p-Tol NaH EtOH cCxCO,EI ~ I N H 58 The other starting materi N 34 33a ~ CI 35; M =metal H P 37 36 You could ,combine these in a linear fashion or in a convergent fashion W'c hoped you' J choose the convergent, perhaps like this, via 39 and 40 Nucleophilic suhstitution is possible on the pyridine 36 but not on a bronlobenzene Protection of the OH in 40 nlight be needed Br U+ OBr ~ I ~ ClO I: : N.r:: CI I HO N 38 34 ~C02H 36 + P Mg, Cu(J) 39 base 37 )vto",Q 40 - 33 OH The Key Reaction Strategy: Diels-Alder Reactions ,- We saw a synthesis of a lycoranc 41 in the textbook that had the Diels-Alder reaction as the key step Stork's synthesis4 also uses the Diels-Alder reaction but in a con1pletely different \vay Stork did no prelin1inary disconnections but sin1ply inserted one alkene and one carbonyl grc)up into the structure to 111ake a Diels-Alder disconnection ideal Prohlenl 40.5: 'Can you suggest \vhere to put 'the alkene and the carbonyl group? o